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Title

OmpA of Uropathogenic Escherichia coli Promotes Intracellular Pathogenesis, Resistance to Cathelicidin, and an IL-17/IL-23 Based Inflammatory Response Permissive for Persistent Infection

Date of Award

Spring 5-15-2010

Author's School

Graduate School of Arts and Sciences

Author's Department

Biology & Biomedical Sciences (Molecular Microbiology & Microbial Pathogenesis)

Degree Name

Doctor of Philosophy (PhD)

Degree Type

Dissertation

Abstract

Urinary tract infections are among the most common bacterial infections, responsible for considerable morbidity and cost among the U.S. patient population. These ailments are typically caused by uropathogenic Escherichia coli (UPEC), which employ a complex intracellular invasion strategy to evade host defenses and the action of antibiotics. In a murine model of cystitis introduction of UPEC can lead to chronic infection, characterized by establishment of quiescent bacterial reservoirs within bladder tissue, which can subsequently cause recurrent UTI.

We have identified the UPEC outer membrane protein A (OmpA) as a critical determinant of virulence for UPEC in establishing and maintaining chronic infection within bladder uroepithelium. Deletion of ompA did not disrupt initial binding and invasion of bladder epithelium by UPEC, but precluded formation of intracellular bacterial communities (IBCs) and attenuated the ability of UPEC to cause persistent infection. This defect in persistence was enhanced in competitive co-infections with wild-type UPEC, resulting in earlier selective clearance of the ompA mutant. Successful intracellular infection with wild-type UPEC elicited a pro-inflammatory, IL-17/IL-23- driven host response that led to enhanced neutrophil recruitment, but also appeared to be permissive for the chronic active phenotype. In contrast, the IBC-deficient ompA mutant triggered a notably dampened cytokine response and was correspondingly unable to establish chronic active infection. Infection of Toll-like receptor 4-deficient C3H/HeJ mice partially restored IBC formation to the ompA mutant, but failed to rescue bacterial persistence in single or competitive infections. In seeking an alternative mechanism for failure of persistence of this mutant, we demonstrated increased susceptibility of the ompA mutant to the human cathelicidin LL-37, an antimicrobial peptide secreted in the bladder during UTI. We conclude that OmpA is a key UPEC virulence factor that permits IBC maturation, thereby promoting an IL-17/IL-23-based inflammatory response associated with chronic epithelial infection, and contributes to cathelicidin resistance in the urinary tract.

Language

English (en)

Chair and Committee

David A. Hunstad

Committee Members

Tom Ellenberger, David B. Haslam, Scott J. Hultgren, Deborah J. Lenschow, R. Reid Townsend

Comments

Permanent URL: https://doi.org/10.7936/K7ZC80S2

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